Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation

Biomolecular condensation is involved in various cellular processes; therefore, regulation of condensation is crucial to prevent deleterious protein aggregation and maintain a stable cellular environment. Recently, a class of highly charged proteins, known as heat-resistant obscure (Hero) proteins, was shown to protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero proteins protect other proteins from aggregation remain unknown. In this study, we performed multiscale molecular dynamics (MD) simulations of Hero11, a Hero protein, and the C-terminal low-complexity domain (LCD) of the transactive response DNA-binding protein 43 (TDP-43), a client protein of Hero11, under various conditions to examine their interactions with each other. We found that Hero11 permeates into the condensate formed by the LCD of TDP-43 (TDP-43-LCD) and induces changes in conformation, intermolecular interactions, and dynamics of TDP-43-LCD. We also examined possible Hero11 structures in atomistic and coarse-grained MD simulations and found that Hero11 with a higher fraction of disordered region tends to assemble on the surface of the condensates. Based on the simulation results, we have proposed three possible mechanisms for Hero11's regulatory function: (i) In the dense phase, TDP-43-LCD reduces contact with each other and shows faster diffusion and decondensation due to the repulsive Hero11-Hero11 interactions. (ii) In the dilute phase, the saturation concentration of TDP-43LCD is increased, and its conformation is relatively more extended and variant, induced by the attractive Hero11-TDP-43-LCD interactions. (iii) Hero11 on the surface of small TDP-43-LCD condensates can contribute to avoiding their fusion due to repulsive interactions. The proposed mechanisms provide new insights into the regulation of biomolecular condensation in cells under various conditions.

Automated summary

In this study, the interactions between Hero11 protein and TDP-43-LCD protein were investigated using multiscale molecular dynamics simulations. Three possible regulatory mechanisms of Hero11 were proposed based on the simulation results. It was found that Hero11 can permeate into TDP-43-LCD condensates and induce changes in their conformation, intermolecular interactions, and dynamics. These mechanisms provide new insights into the regulation of biomolecular condensation under different conditions.